Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.

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Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Journal of Biomedical Science ◽

10.1186/s12929-021-00722-w ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Chanon Piamsiri ◽

Chayodom Maneechote ◽

Natthaphat Siri-Angkul ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Myocardial Infarction ◽

Therapeutic Potential ◽

Coronary Perfusion ◽

Beneficial Effects ◽

Cell Death Pathways ◽

Threatening Condition ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

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Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Molecules ◽

10.3390/molecules23123322 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3322 ◽

Cited By ~ 9

Author(s):

Xuguang Li ◽

Tianyi Yuan ◽

Di Chen ◽

Yucai Chen ◽

Shuchan Sun ◽

...

Keyword(s):

Myocardial Infarction ◽

Inflammatory Responses ◽

Therapeutic Option ◽

Crystal Form ◽

Human Coronary Artery ◽

Beneficial Effects ◽

Ppar Γ ◽

Cardioprotective Effects

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

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Abstract 217: Long Non-coding RNA Myocardial Infarction-associated Transcript (MIAT) Protects Cardiac Progenitor Cells From Oxidative Stress-induced Cell Death

Circulation Research ◽

10.1161/res.119.suppl_1.217 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Liu Yang ◽

Yang Yu ◽

Baron Arnone ◽

Chan Boriboun ◽

Jiawei Shi ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Cell Death ◽

Progenitor Cells ◽

Cardiac Cells ◽

Border Zone ◽

Mouse Heart ◽

Cardiac Progenitor Cells

Background: Long non-coding RNAs (lncRNAs) are an emerging class of RNAs with no or limited protein-coding capacity; a few of which have recently been shown to regulate critical biological processes. Myocardial infarction-associated transcript (MIAT) is a conserved mammalian lncRNA, and single nucleotide polymorphisms (SNPs) in 6 loci of this gene have been identified to be strongly associated with the incidence and severity of human myocardial infarction (MI). However, whether and how MIAT impacts on the pathogenesis of MI is unknown. Methods & Results: Quantitative RT-PCR analyses revealed that MIAT is expressed in neonatal mouse heart and to a lesser extent in adult heart. After surgical induction of MI in adult mice, MIAT starts to increase in 2 hours, peaks at 6 hours in atria and 12 hours in ventricles, and decreases to baseline at 24 hours. Fluorescent in situ hybridization (FISH) revealed a slight increase in the number of MIAT-expressing cells in the infarct border zone at 12 hours post-MI. Moreover, qRT-PCR analyses of isolated cardiac cells revealed that MIAT is predominantly expressed in cardiosphere-derived cardiac progenitor cells (CPCs). Treatment of CPCs with H 2 O 2 led to a marked upregulation of MIAT, while knockdown (KD) of MIAT resulted in a significantly impaired cell survival in vitro with H 2 O 2 treatment and in vivo after administered in the ischemic/reperfused heart. Notably, bioinformatics prediction and RNA immunoprecipitation identified FUS (fused in sarcoma) as a novel MIAT-interacting protein. FUS-KD CPCs displayed reduced cell viability and increased apoptosis under oxidative stress. Furthermore, MIAT overexpression enhanced survival of WT CPCs but not FUS-KD CPCs, suggesting that the protective role of MIAT is mediated by FUS. Conclusions: MIAT interacts with FUS to protect CPCs from oxidative stress-induced cell death.

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Abstract 17202: Synthetic Modified RNA Driven Delivery of Insulin-Like Growth Factor-1 Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.17202 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Chien-Ling Huang ◽

Anne-Laure Leblond ◽

Elizebeth C Turner ◽

Arun H Kumar ◽

Donnchadh M O’Sullivan ◽

...

Keyword(s):

Myocardial Infarction ◽

Growth Factor ◽

Border Zone ◽

Insulin Like Growth Factor ◽

Area At Risk ◽

Akt Phosphorylation ◽

Post Transfection ◽

Erk Phosphorylation ◽

Induced Apoptosis

To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic modified RNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in a murine model of MI. Transient transfection of synthetic GFP modRNA as an tracking indicator, with polyethylenimine (PEI)-based nanoparticle, showed efficient delivery of modRNA derived protein and minimum cytotoxicity in HL-1 cardiomyocytes (CM; 44±5%). ModRNA-IGF1 protein expression and secreted levels increased 3.5 fold ( p <0.05) at 24 hours and peaked at 48 hours post-transfection. The expression efficiency of modRNA was further enhanced (~2 fold at 24 hours post-transfection; p <0.05) under hypoxia-induced apoptosis conditions. ModRNA augmented secreted and cell associated IGF1 promoting CM survival and abrogating cell apoptosis (71±5% in controls to 37±7%, p <0.05). Translation of modRNA-IGF1 was sufficient to induce downstream increases in Akt and Erk phosphorylation (3 fold and 2 fold, respectively; p <0.01). Downregulation of IGF1 specific miRNA-1 and -133 (52% and 56%, respectively; p <0.01) but not miR-145 expression, was also confirmed. As proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased in TUNEL-positive cells within the infarct border zone (BZ) at 24 hours (22±3% versus 53±8% in controls, p <0.01). Akt phosphorylation was augmented while caspase-9 activity and cleavage was downregulated in the infarct BZ compared to controls ( p <0.05). These findings demonstrate extended in vivo cytoprotective effect of IGF1 24 hours post-MI driven by synthetic modRNA delivery. This provides a novel strategy to reduce ischemic injury by controlled release of IGF1 using a controllable bioactive nanoparticle for ‘short burst’ IGF1 cytoprotective therapy.

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Abstract 1096: Cytokine Enhancement with Hgf Or Vegf in the Infarct Border Zone is Key to Attenuating the Negative Remodelling after Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_646 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Sonja Schrepfer ◽

Tobias Deuse ◽

Christoph Peter ◽

William Stein ◽

Tim Doyle ◽

...

Keyword(s):

Myocardial Infarction ◽

Treatment Strategies ◽

Border Zone ◽

Cytokine Release ◽

Intramyocardial Injection ◽

Paracrine Effects ◽

Infarct Border Zone ◽

Infarct Border

Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×106 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.

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Abstract 2672: Serial in vivo Non-invasive Imaging of Intramyocardially Injected Autologous Mesenchymal Stem Cells, Modified for Transgene Expression of Positron-Emission Tomography (PET) Reporter in Porcine Myocardial Infarction

Circulation ◽

10.1161/circ.116.suppl_16.ii_592-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Mariann Gyongyosi ◽

Jeronimo Blanco ◽

Terez Marian ◽

Ors Petnehazy ◽

Rayyan Hemetsberger ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Pet Imaging ◽

Transgene Expression ◽

Lentiviral Vector ◽

Border Zone ◽

Percutaneous Balloon ◽

Diffuse Distribution

Objective. The aim of our study was to elaborate an in vivo tracking method of the intramyocardially injected msenchymal stem cells (MSCs), modified for transgene expression of trifusion protein (lentiviral vector, expressing renilla luciferase /RL/, red fluoroscein protein /RFP/ and herpes simplex truncated thymidine kinase /tTK, positron emmission tomography PET-reporter gene/) using serial PET imaging in pig myocardial infarction (MI). Methods. Bone marrow (100 ml) was harvested from pigs immediately before induction of MI by percutaneous balloon occlusion of the LAD followed by reperfusion. The MSCs were selected and cultivated. The lentiviral vector LV-RL-RFP-tTK was inoculated into the MSCs under control of CMV promoter. The cells with the highest fluorescence intensity (after achieving appr. 50% transfection efficacy) were sorted, and tracked in vitro by PET using 9-(4-[18F]fluoro-3-hydroxymethylbutyl)-guanine (18FHBG). The transfected MSCs (at least 3 mio MSCs/ pigs) were then injected direct intramyocardially using NOGA electromagnetic guidance in pigs in 10 locations of the infarct border zone (min. 0.3 million cells/injection), followed by PET imaging 30 hours and 7 days later, after intravenous injection of 5 mCi 18FHBG. Results. The in vitro 18FHBG uptakes of the transgene modified MSCs by PET were 10 times larger than the control JY human B-lymphoblasts and T lymphocytes. The minimum number of the cells detectable with PET was 0.2 million. MRI of the pigs revealed a mean global EF of 47+/-3.5%. PET imaging displayed diffuse distribution of the injected MSCs with high activity of the PET tracer in the anterior wall and septum at 30h, and less tracer activity in the injections sites with diffuse distribution in the pericardium and pleura indicating the wandering of the living cells at 7 days. PET imaging did not show 18FHBG accumulation in the infarcted heart of the control animals. Myocardial histology with RL and RFP staining confirmed the distribution of the injected MSCs through an elongated track around the injected area, 9 days after delivery. Conclusion. In vivo tracking of gene-modified porcine MSCs by PET imaging is feasible and allows serial noninvasive imaging of homing and propagation of MSCs in pigs after MI.

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Argon Exposure Induces Postconditioning in Myocardial Ischemia–Reperfusion

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248417702891 ◽

2017 ◽

Vol 22 (6) ◽

pp. 564-573 ◽

Cited By ~ 6

Author(s):

Sandrine Lemoine ◽

Katrien Blanchart ◽

Mathieu Souplis ◽

Adrien Lemaitre ◽

Damien Legallois ◽

...

Keyword(s):

Myocardial Infarction ◽

Ischemia Reperfusion ◽

Contractile Force ◽

Left Ventricular ◽

Border Zone ◽

Left Ventricular Ejection ◽

Human Atrial Appendages ◽

Hypoxia Reoxygenation

Background and Purpose: Cardioprotection against ischemia–reperfusion (I/R) damages remains a major concern during prehospital management of acute myocardial infarction. Noble gases have shown beneficial effects in preconditioning studies. Because emergency proceedings in the context of myocardial infarction require postconditioning strategies, we evaluated the effects of argon in such protocols on mammalian cardiac tissue. Experimental Approaches: In rat, cardiac I/R was induced in vivo by transient coronary artery ligature and cardiac functions were evaluated by magnetic resonance imaging. Hypoxia–reoxygenation (H/R)-induced arrhythmias were evaluated in vitro using intracellular microelectrodes on both rat-isolated ventricle and a model of border zone in guinea pig ventricle. Hypoxia–reoxygenation loss of contractile force was assessed in human atrial appendages. In those models, postconditioning was induced by 5 minutes application of argon at the time of reperfusion. Key Results: In the in vivo model, I/R produced left ventricular ejection fraction decrease (24%) and wall motion score increase (36%) which was prevented when argon was applied in postconditioning. In vitro, argon postconditioning abolished H/R-induced arrhythmias such as early after depolarizations, conduction blocks, and reentries. Recovery of contractile force in human atrial appendages after H/R was enhanced in the argon group, increasing from 51% ± 2% in the nonconditioned group to 83% ± 7% in the argon-treated group ( P < .001). This effect of argon was abolished in the presence of wortmannin and PD98059 which inhibit prosurvival phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and MEK/extracellular receptor kinase 1/2 (ERK 1/2), respectively, or in the presence of the mitochondrial permeability transition pore opener atractyloside, suggesting the involvement of the reperfusion injury salvage kinase pathway. Conclusion and Implications: Argon has strong cardioprotective properties when applied in conditions of postconditioning and thus appears as a potential therapeutic tool in I/R situations.

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Erythropoietin supports the growth and function of Sca-1+ stem cells and promotes myocardial infarction repair in mice

10.21203/rs.3.rs-42457/v1 ◽

2020 ◽

Author(s):

Lin Zuo ◽

Duan-duan Li ◽

Xiu-Xia Ma ◽

Shan-Hui Shi ◽

Ding-Chao Lü ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Border Zone ◽

Adult Mice ◽

P38mapk Signaling ◽

And Performance ◽

Long Acting ◽

And Function

Abstract Background：Myocardial infarction (MI) is the leading cause of death in the world-wide population. With the improvement of clinical therapy, the mortality in acute MI cases has been significantly reduced. This study was to demonstrate that erythropoietin (EPO) is an effective supporter for Sca-1+ stem cells (SCs) and can promote the repair of myocardial infarction (MI) partially via way of enhancing Sca-1+ SCs activities. Methods: Darbepoetin alpha (a long-acting EPO analog, EPOanlg) (30 mg/kg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocytes apoptosis and regenerations and microvessels density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mice hearts and were respectively used to identify the colony forming ability and the supporting effect of EPO on these Sca-1+ SCs. Results: Compared to MI alone, EPOanlg reduced the infarct percentage and cardiomyocyte apoptosis ratio and LV chamber dilatation, improved cardiac performance, increased the regenerated cardiomyocyte ratio in the border zone and the numbers of coronary microvessels, while without obvious adverse effects in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and Stat5-p38MAPK signaling. Conclusions: EPO promotes Sca-1+ SCs activities and MI repair. The study enlightens the prospects of Sca-1+ SC supporters in the treatment of MI.

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Abstract 413: Podoplanin Neutralization Improves Cardiac Remodeling and Function After Acute Myocardial Infarction

Circulation Research ◽

10.1161/res.121.suppl_1.413 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Maria Cimini ◽

Venkata N Garikipati ◽

Suresh K Verma ◽

Cindy Benedict ◽

Zhongjian Cheng ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Magnetic Beads ◽

Neutralizing Antibody ◽

Treated Group ◽

Border Zone ◽

Control Group ◽

Type I

Variety of cardioprotective and reparative therapeutic approaches have emerged for the treatment of cardiac remodeling after myocardial infarction (MI). Here we propose a novel mechanism using a neutralizing antibody that target Podoplanin (PDPN), a platelet aggregation-inducing type I transmembrane glycoprotein, expressed on a cohort of myocardial cells that migrate to the infarcted area after MI and contribute significantly to scar formation. The PDPN+ cells were isolated from infarcted hearts two days after MI, using magnetic beads sorting. We tested in vitro the effect of PDPN neutralizing antibody (5μg/ml) in a transwell migration assay and the activation of monocytes co-cultured with PDPN+ cells. The neutralizing antibody decreased significantly PDPN+ cells migration. Monocytes co-cultured with PDPN+ cells produced high levels of IL1α and IL12, whereas treatment of co-cultures with podoplanin neutralizing antibody inhibited IL1α and IL12 production and increased IL9 and IL10 production, suggesting a switch form pro-inflammatory to anti-inlammatory phenotype. To tests the effect of podoplanin neutralizing antibody in vivo, C57BL/6 wild type mice were subjected to experimental MI and anti-PDPN antibody (25μg/ml) was injected i.p. on days 1, 2, 7 and 15 after MI and mice were scarified two months after. At 7 days after MI echocardiography revealed comparable ~30% of ejection fraction (EF) in control and antibody-injected mice. After one month EF% remained unchanged in control group and increased up to 45% in antibody-treated group, suggesting improvement in cardiac function. Histologically, in the control group the ischemic area was composed by fibrotic tissue highly positive for fibronectin and αSMA, whereas in the antibody-treated group revealed large number of survived, as well as proliferating myocytes expressing αSARC-actin and Phospho-H3. Further, there was a significant increase in CD31 positive cells in the infarct border-zone of antibody-treated vs. control hearts, suggesting increased angiogenesis. Our findings suggest that inhibition of PDPN during first two weeks after MI intensely enhances cardiac regeneration and angiogenesis. This may represent a new therapeutic support for the tissue renewal after MI.

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Erythropoietin supports the growth and function of Sca-1+ stem cells and promotes myocardial infarction repair in mice

10.21203/rs.3.rs-42457/v2 ◽

2020 ◽

Author(s):

Lin Zuo ◽

Duan-duan Li ◽

Xiu-Xia Ma ◽

Shan-Hui Shi ◽

Ding-Chao Lü ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Border Zone ◽

Adult Mice ◽

P38mapk Signaling ◽

And Performance ◽

Long Acting ◽

And Function

Abstract Background：Myocardial infarction (MI) is the leading cause of death in the world-wide population. With the improvement of clinical therapy, the mortality in acute MI cases has been significantly reduced. This study was to demonstrate that erythropoietin (EPO) is an effective supporter for Sca-1+ stem cells (SCs) and can promote the repair of myocardial infarction (MI) partially via the way of enhancing Sca-1+ SCs activities. Methods: Darbepoetin alpha (a long-acting EPO analog, EPOanlg) (30 mg/kg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocytes apoptosis and regenerations and microvessels density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mice hearts and were respectively used to identify the colony forming ability and the supporting effect of EPO on these Sca-1+ SCs. Results: Compared to MI alone, EPOanlg reduced the infarct percentage and cardiomyocyte apoptosis ratio and LV chamber dilatation, improved cardiac performance, increased the regenerated cardiomyocyte ratio in the border zone and the numbers of coronary microvessels, while without obvious adverse effects in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and Stat5-p38MAPK signaling. Conclusions: EPO promotes Sca-1+ SCs activities and MI repair. The study enlightens the prospects of Sca-1+ SC supporters in the treatment of MI.

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